The goal of this proposal is to continue a Clinical Center of TrialNet at the University of California at San Francisco (UCSF), with the ultimate long-term objectives to better understand the natural history and pathogenesis of type 1 diabetes mellitus (T1D), and to develop therapies to preserve endogenous insulin secretion in those with new onset T1D, and to prevent (T1D). UCSF is uniquely positioned to serve as a Clinical Center for TrialNet, given a well renowned clinical diabetes program;a large population base for subject recruitment;and a strong established track record with clinical research and autoimmune interventions for T1D. In addition, the center has Clinical and Translational Science Institute (CTSI) funding, with both a Pediatric and General Clinical Research Center (PCRC, GCRC), and investigators with extensive experience in both basic science and clinical research. This proposal will extend UCSF's past role as a Clinical Center in TrialNet. Specifically, the study goals are: Specific Aim 1) To continue in our role as a Clinical Center for TrialNet, completing existing studies and developing and implementing new protocols in the network. To that end, we will continue our present plans to maximize recruitment for studies by increasing awareness amongst health care professionals and affected subjects and families. We will continue to foster relationships with a large affiliated network throughout Northern California and the Pacific Islands. We will recruit, enroll, and retain subjects within these studies according to the highest GCP standards. Specific Aim 2: We propose a novel phase II study to determine the safety and efficacy of Imatinib in preserving endogenous beta cell function in subjects with new onset T1D. This tyrosine kinase inhibitor has proven highly effective in therapy for specific cancers, and has more recently been shown to modulate autoimmunity in pre-clinical and clinical settings. In the NOD mouse, Imatinib induces remission in animals with new onset DM, and the drug can be withdrawn with the animals sustaining a durable remission, suggesting that it is tolerizing. We propose a multi-center, double-arm, blinded, placebo-controlled, 2:1 randomized, phase II clinical trial for individuals with recent onset T1D. PUBLIC HEALTH RELEVANCE: Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease in which insulin producing beta cells are completely destroyed by autoreactive T cells, resulting in a dependence on exogenous insulin for life. Current management of T1D is not optimal, with risk for recurrent hypoglycemia and long term complications relating to chronic hyperglycemia. The goals of the proposed studies are to prevent T1D, or to preserve endogenous insulin secretion in those with recent onset disease, so as to prevent the morbidity and mortality associated with this condition.